The field of tumor immunotherapy is progressing rapidly. New pathways and molecular targets are being identified for translation and treatment, and more are urgently needed. With this growing level of insight comes the pressing need for molecularly-defined, scientifically rigorous in vivo preclinical models, in which to discover new mechanisms, and test the new hypotheses. Even though our current ?single-agent? approach can be dramatic in some patients, most of the patients, with most kinds of tumors, do not yet receive any benefit from immunotherapy. Thus, to move the field forward to the next level of clinical efficacy, the emphasis will be on discovering new targets; identifying synergistic combinations; and finding ways to integrate innovative immunotherapy with standard-of-care chemotherapy and radiation. The PI, Dr. Madhav Sharma, is a senior and highly productive Principle Research Scientist (non-tenure track), who has been associated for 17 years with the laboratory of the Unit Director, Dr. David Munn. As a research specialist in this group, Dr. Sharma has developed sophisticated preclinical models in tumor immunology, and used these for high-impact, innovative new basic-science discoveries, with high translational potential. The current proposal focuses on a novel population of potently immunogenic dendritic cells (DCs), arising in tumors during immunotherapy. These share attributes of ?conventional? CD103+ cDCs, but they differentiate directly from monocytic MDSCs, already pre-positioned in the tumor, in response to inflammation. The scientific premise of the proposal is that this specialized population of myeloid-lineage Ly6c+CD103+ DCs is a critical driver of anti-tumor immune responses during multiple forms of immunotherapy, in both mice and humans; and that it is possible to therapeutically amplify the number of these cells in the tumor, so as to markedly enhance the effectiveness of immunotherapy. The translational importance of these findings is that they identify the transcription factor p53 in host myeloid-lineage cells as the key driver of this Ly6c+CD103+ DC population; thus revealing myeloid-lineage p53 as a previously unsuspected target for immunotherapy. Myeloid p53 can be efficiently targeted by re-purposing existing p53-agonist (MDM2-inhibitor) drugs already under clinical development for other indications. All of these innovative preclinical discoveries have resulted directly from Dr. Sharma?s sustained and highly productive program of preclinical research in Dr. Munn?s group.